Non-Enzymatic Oxidation of a Pentagalloylglucose Analogue into Members of the Ellagitannin Family

Article abstract of DOI:10.1002/anie.201708703

The occurrence of more than 1000 structurally diverse ellagitannins has been hypothesized to begin with the oxidation of penta-O-galloyl-β-d-glucose (β-PGG) for the coupling of the galloyl groups. However, the non-enzymatic behavior of β-PGG in the oxidation is unknown. Disclosed herein is which galloyl groups tended to couple and which axial chirality was predominant in the derived hexahydroxydiphenoyl groups when an analogue of β-PGG was subjected to oxidation. The galloyl groups coupled in the following order: at the 4,6-, 1,6-, 1,2-, 2,3-, and 3,6-positions with respective S-, S-, R-, S-, and R-axial chirality. Among them, the most preferred 4,6-coupling reflected the what was observed for natural ellagitannins. A new finding was that the second best coupling occured at the 1,6-positions. With the detection of a 3,6-coupled product, this work demonstrated that even ellagitannin skeletons with an axial-rich glucose core may be generated non-enzymatically.

Full text of DOI:10.1002/anie.201708703

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Non-enzymatic Oxidation of a Pentagalloylglucose Analog to
Ellagitannins
Authors: Seiya Ashibe, Kazutada Ikeuchi, Yuji Kume, Shinnosuke
Wakamori, Yuri Ueno, Takashi Iwashita, and Hidetoshi
Yamada
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708703
Angew. Chem. 10.1002/ange.201708703
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10.1002/anie.201708703
Angewandte Chemie International Edition
COMMUNICATION
Non-enzymatic Oxidation of a Pentagalloylglucose Analog to
Ellagitannins
Seiya Ashibe,[a] Kazutada Ikeuchi,[a] Yuji Kume,[a] Shinnosuke Wakamori,[a] Yuri Ueno,[a] Takashi
Iwashita,[b] and Hidetoshi Yamada*[a]
OG
Abstract: The occurrence of more than 1,000 structural diversity in
ellagitannins has been hypothesized to begin with oxidation of penta-
O-galloyl-b-D-glucose (b-PGG) to couple the galloyl groups. However,
the non-enzymatic behavior of b-PGG in the oxidation is unknown.
Here, we disclose which galloyl groups on glucose tended to couple
and which axial chirality was predominant in the derived
hexahydroxydiphenoyl groups, when an analog of b-PGG was
subjected to oxidation. The study revealed that the galloyl groups
coupled, in the following order of production ratio: at the 4,6-, 1,6-,
1,2-, 2,3-, and 3,6-positions with respective S, S, R, S, and R-axial
chirality. Among them, the most preferred 4,6-coupling reflected the
tendency observed in natural ellagitannins. An astonishing fact was
that the second best was the 1,6-coupling. With the detection of a 3,6-
coupled product, this work demonstrated that even ellagitannin
skeletons with an axial-rich glucose core may generate non-
enzymatically.
HO
O
1st
OH
phase
OG
OG
OH
HO
Basic ellagitannins
O
OH
OH
GO
Oxidation
Coupling
of G
O
HHDP
OH
O
group
6
HO
HO
OH
OG
OG
O
1
O
HO
HO
β-PGG (1)
HO
GO
OG
O
O
O
O
davidiin (2)
G = HO
HO
CO2
O
O
OG
O
O
O
HO
HO
The mimic in this work (5)
HO
HO
HO
OH
OH
G = BnO
CO2
OH
HO
HO
OH
casuarictin (3)
HO
HO
HO
O
O
O
O
O
2nd
phase
OG
GO
OG
Explosive increase
of diversity
tellimagrandin II (4)
Ellagitannins are a class of hydrolysable tannins. A broad range
of activities have been associated with ellagitannins, such as
therapeutic, antioxidant, and tanning activities.[1–4] Compounds of
the class have structural diversity as more than 1,000 are known.
The diversity has been explained to arise in phases. The first phase
is oxidation of 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (b-
PGG, 1) to form the hexahydroxydiphenoyl (HHDP) group (Figure
1) as proposed by Schmidt and Haslam.[5–7] The basic
ellagitannins, supplied in the first phase, are then further modified
to increase the diversity explosively,[8] which is the second phase.
In the first phase, two of the five galloyl groups of 1 couple on the
glucose core; therefore, the positional variety of the HHDP groups
represents the beginning of the huge structural diversity.
Interestingly, coupling takes place even between galloyl groups
on discontiguous hydroxy groups to form 'axial-rich' ellagitannins,
such as davidiin (2).[9–11] Formation of the second HHDP group is
also allowed as casuarictin (3). The HHDP group has axial
chirality, which is supposed to be induced by conformational
constraints within 1.[12]
Figure 1. Stepwise occurrence of structural diversity in ellagitannin biosynthesis.
Verification of the proposal, the Schmidt-Haslam hypothesis,
is insufficient. The sole reliable verification was reported by
Niemetz and Gross.[13,14] They elucidated enzymatic oxidation of
1 to demonstrate the validity of the hypothesis for the first time by
isolation of tellimagrandin II (4). However, since this very
important progress in this field, no further evidence has been
reported. In particular, production of the axial-rich ellagitannins
from 1 is still in the suppositional level. For the axial chirality of the
HHDP group, it seems that synthetic works have verified the
hypothesis by showing that the couplings at the 1,6-,[15] 2,3-,[16,17]
3,4-,[18] 3,6-,[19,20] and 4,6-positions[21–24] almost reflect the axial
chirality in natural products. However, the verification is deficient
because all reactants used in the synthetic works are partly
galloylated glucose, which cannot mimic the reaction of fully
galloylated 1. Although a simple chemical reaction cannot reflect
the biosynthesis where enzymes may take charge of the
transformations, it is important to understand behaviors in non-
enzymatic oxidation of 1 in the process of clarifying the
biosyntheses of ellagitannins because the galloyl group also can
couple non-enzymatically. However, simple oxidation of
unprotected galloyl groups produces various types of reaction
products to make analysis focused on the oxidation products
difficult. In this study, we investigated non-enzymatic oxidation of
5 (Figure 1), an analog of 1, and revealed which 4-O-benzylated
galloyl groups tended to couple and which axial chirality was
predominant in respective coupling positions.
[a]
[b]
Mr. S. Ashibe, Prof. Dr. K. Ikeuchi, Mr. Y. Kume, Dr. S. Wakamori,
Ms. Y. Ueno, Prof. Dr. H. Yamada
School of Science and Technology
Kwansei Gakuin University
2-1 Gakuen, Sanda 669-1337, Japan
E-mail: hidetosh@kwansei.ac.jp
Dr. T. Iwashita
Bioorganic Research Institute
Suntory Foundation for Life Sciences
8-1-1 Seikadai, Seika-cho, Soraku-gun, Kyoto 619-0284, Japan
Supporting information and the ORCID identification numbers for the
authors of this article is given via a link at the end of the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708703
Angewandte Chemie International Edition
COMMUNICATION
3JH–H (Hz)
OBn
OR
A
B
5 m/z = 1389.3 [M – H]–
H-1–H-2: 8.5
H-2–H-3: 9.2
H-3–H-4: 10.1
H-4–H-5: 9.8
3JH–H (Hz)
HO
HO
OH
HO
HO
OH
D
CuCl2, nBuNH2
H-1–H-2: 7.6
H-2–H-3: 9.9
H-3–H-4: 9.9
H-4–H-5: 9.9
S
S
BnO
HO
RO
HO
C
MeOH
60
40
20
RT, 30 min
O
O
O
O
O
O
O
O
O
OH
H
B
9
OR
OH
O
O
O
O
7
OH
OBn
O
O
H
A
HO
BnO
1
3
C
23
O
O
HO
RO
H
O
O
C
E
H
O
21
O
O
: R = Bn
0
7
R
OH
OH
6
S
0
20
40
60
80
100
(min)
Retention time
HO
HO
HO
H2, Pd/C
acetone, 76%
Column: YMC-Pack Pro C18 RS
Size: 250 × 4.6 mm
Detection: 254 nm
Eluant: MeOH/H2O/TFA
= 72/28/0.05
OH
HO
OBn
OR
m/z =
m/z =
: HMBC
: ROESY
Confirmation of axial chirality
see Scheme 1
3: R = H
(casuarictin)
1385.3 [M – H]– 1387.3 [M – H]–
3JH–H (Hz)
H-1–H-2: 8.2
OH H-2–H-3: 9.6
E
BnO
HO
C
D
RO
HO
OH
OR
OBn
HO
OH
OH
R
HO
HO
20
S
32
H-3–H-4: 9.9
H-4–H-5: 10.1
OR
OH
23
S
34
OH
O
H
H
RO
HO
H
O
C
HO
RO
22
C
O
O
O
C
H
21
O
OH
H-6:
O
H
3JH–H (Hz)
O
O
O
6
O
O
O
δ 5.37 & 3.95
O
OR
OH
6
6
H-1–H-2: 3.4
H-2–H-3: 0
H-3–H-4: 3.2
H-4–H-5: 0
3JH–H (Hz)
OH
O
O
O
O
O
O
HO
H
H
H-1–H-2: 2.5
H-2–H-3: 6.0
H-3–H-4: 6.0
H-4–H-5: 2.1
3
O
O
O
H
O
O
OBn
O
O
O
O
O
OH
O
O
HO
RO
OH
OR
O
OH
HO
HO
OH
OBn
OH
8: R = Bn
OH
OH HO
HO
OH
RO
OR
BnO
: R = Bn
10
9
H2, Pd(OH)2
MeOH, 93%
H2, Pd(OH)2
MeOH, 96%
4: R = H (tellimagrandin II)
2: R = H (davidiin)
Figure 2. Chromatogram and products obtained from oxidation of 5.
For the coupling of galloyl groups of 5, we adopted a reaction
induced by CuCl2–nBuNH2 (Figure 2).[20] This coupling reaction was
suitable for a study aimed at understanding the non-enzymatic
oxidation of the b-PGG analog because the reaction (1) proceeds
effectively at room temperature, when thermal conditions are
similar to those of biosynthesis, (2) has a feature that makes
coupling of galloyl groups spatially close, and (3) has been
applied in syntheses of natural ellagitannins for coupling galloyl
groups on the varied positions of glucose.[15,18,24–28]
compound, the structures of which were determined as follows.
The other peaks were composed of multiple compounds.
The compound of the peak A (compound A) possessed the
1,2-O- and 4,6-O-HHDP (1,2:4,6-O-HHDP) groups (Figure 2). As
mentioned, this compound had two HHDP groups; hence, the
number of the galloyl group was one. The HMBC spectrum of the
compound (SI-3.4) displayed two definite correlations at H-3/C-21
and C-21/H-23 (see SI-2 for the numbering) to indicate that the
galloyl group was on O-3. According to this information, the
structure of compound A had either the 1,2:4,6-, 1,4:2,6- or the
1,6:2,4-O-HHDP bridge. Of these, the 1,4:2,6- and 1,6:2,4-
bridged isomer could be excluded because bridging at these
positions does not allow pyranose ring to remain in the 4C1-
The oxidation of 5 with CuCl2 and nBuNH2 provided a
complicated mixture of products (Figure 2). We conducted the
reaction after optimization to completely consume 5 because
residual reactant would make separation of the products
increasingly difficult. The products were separable using HPLC
with a reverse phase column (YMC-Pack Pro C18 RS) eluted with
MeOH/H2O/TFA (v/v/v 72/28/0.05) and detected at 254 nm. Mass
spectra indicated that compounds eluted before 48 min lost one
or more galloyl and HHDP groups. The loss of the groups was
due to solvolysis, a known side reaction of the coupling
reaction.[24] The molecular ions corresponding to the peaks
observed between 48 to 75 min and after 75 min were at m/z
1385.3 and 1387.3, respectively, whose values were 4- and 2-
mass smaller than that of 5. Therefore, compounds eluted
between 48 and 75 min had two HHDP groups, and that eluted
between 75 to 120 min had one HHDP group. 1H NMR spectra of
separated fractions showed that peaks A–E included each single
conformation that the coupling constants (3JH–H
) between
hydrogens on the glucopyranose ring suggested. Therefore,
compound A had the 1,2:4,6-O-HHDP bridges. An ellagitannin,
roxbin B, has been reported to have the skeleton;[29] however, the
structure was revised to a 2,3:4,6-HHDP isomer,[30] and thus
natural roxbin B could not be used as an authentic sample for
identification of compound A.
Therefore, we confirmed that the structure of compound A
was 6 through synthesis. Prior to the synthesis, we estimated that
the axial chirality of the 4,6-O-HHDP group was S on the basis of
frequency of appearance in natural products. For the 1,2-O-
HHDP group, we synthesized both R- and S-isomers, of which the
synthesis of the R-isomer is summarized in Scheme 1. The
synthesis commenced with the preparation of allyl- and benzyl-
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10.1002/anie.201708703
Angewandte Chemie International Edition
COMMUNICATION
a.
OMe
O
MeO
O
HO2C CO2H
protected (R)-HHDP diacid (R)-12 and its anhydride 13 from
known 11 (Scheme 1, a).[25,31] Thus, hydrolysis of 11 released (R)-
12, treatment of which with oxalyl chloride provided 13. On the
other hand, 3-O of diacetone glucose (14) was acylated with 3,5-
di-O-allyl-4-O-benzylgallic acid[25] to furnish 15 (Scheme 1, b).
After removal of the acetonide groups from 15, the 4,6-diol of 16
was protected as p-methoxybenzylidene acetal to give 17.
Treatment of 17 with acid anhydride 13 constructed b-
glucosylester 18. The subsequent intramolecular lactonization of
18 produced 1,2-bridged 19. The removal of the p-
methoxybenzylidene group provided 4,6-diol 20. Double
esterification of the exposed diol with diacid (S)-12 to give 21
followed by removal of all the allyl groups afforded 6. The 1H NMR
spectrum was identical to that of the compound A (SI-3.18).
Therefore, the structure of compound A was 6 with the R- and S-
axial chiralities of the 1,2- and 4,6-O-HHDP groups, respectively. In
addition, we removed all benzyl groups from 6 to provided
unprotected artificial ellagitannin 22.
NaOH, H2O
MeOH, THF;
AllO
OAll
H3O+, 72%
O
BnO AllO OAll OBn
O
(R)-12
(COCl)2 toluene
AllO
O
R
O
O
O
All
BnO AllO OAll OBn
11
AllO
OAll
BnO AllO OAll OBn
b.
13
O
H
O
i PrOH, aq HCl
HO
HO
(All2Bn)GO
O
O
H
O
R1O
O
THF, 88%
OH
HO
14: R1 = H
16
O
O
MP
OMe
HO
MeO
CSA, DMF, 72%
OBn
OMe
O
G(All2Bn)
MP
O
O
O
(All2Bn)GO
EDCI·HCl, DMAP
CH2Cl2, 94%
The compound of the peak B was 7 (Figure 2). The mass
spectrum indicated the existence of two HHDP groups. The
HMBC correlations were observed at H-1/C-7 and C-7/H-9 (SI-
3.5) and illustrated that the galloyl group was on O-1, and thus the
two HHDP groups were on O-2, -3, -4, and -6. Among the
conceivable bridging patterns of the HHDP groups, the 2,3:4,6-
bridged isomer was plausible because of its 4C1-glucose core
OH
HO
15: R1 = G(All2Bn)
17
13, Et3N, CH2Cl2
R2O
MP
O
R2O
O
O
O
O
OAll
O
O
O
O
OAll
HO
HO
(All2Bn)G
(All2Bn)G
O
O
O
O
OBn
OBn
3
EDCI·HCl
DMAP
indicated by the JH–H values; therefore, the compound
OAll
OAll
OAll
OAll
corresponded to casuarictin (3).[32] Removal of the benzyl groups
from 7 provided a product that was identical to natural 3 (SI-3.20)
and which confirmed the structure, including the two S-axial
chiralities of the HHDP groups.
AllO
AllO
CH2Cl2
23% (2 steps)
OBn
OBn
19: R2 = MP–CH
18
1) i PrOH, aq HCl, THF
86% for 20: R2 = H
OH
O
HO
HO
The compounds of the peaks C and D were 8 and 9,
respectively. These structures were confirmed with their S-axial
chiralities by their transformation to known natural products as
well as the plot for structural determination of 7. According to the
2) (S)-12
OH
HO
EDCI·HCl, DMAP
OBn
CH2Cl2, 64%
AllO
OAll
OAll
for 21: R2
=
HO
O
O
BnO
3
CO2
CO2
mass spectrum, 8 and 9 had one HHDP group. For 8, the JH–H
O
O
AllO
3) Pd(PPh3)4
OH
OH
O
4
O
values indicated that the glucose was in the C1-form. The large
HO
HO
O
O
1
O
O
difference of H NMR chemical shifts of two hydrogen atoms on
MeN NMe
O
C-6 suggested the 4,6-position for the HHDP group.[29,33]
Therefore, the structure corresponded to tellimagrandin II (4).[34]
For 9, the HMBC correlations appeared at H-6/C-22 and C-22/H-
20 (SI-3.7) to show that one of the connecting positions of the
O
CH2Cl2, 54%
O
OH
OH
HO
6
22
HO
H2, Pd/C, acetone, 92%
OH
3
HHDP group was O-6. The JH–H values suggested the
Scheme 1. Synthesis of 6 and 22.
occurrence of an axial-rich pyranose. The 1H NMR spectra of
debenzylated 4 and 2 were identical to that of tellimagrandin II (4)
synthesized by the Feldman’s group[35] and to that of natural
davidiin (2),[9,10,15] respectively (SI-3.21 and 3.22).
addition, comparison of the NMR data of natural products bearing
R-[36] or S-axial chirality[37] to that of 10 supported the R-axial
chirality.
The compound of the peak E was 10. The 3JH–H values of 1H
NMR between protons on the pyranose were small, suggesting
that it was an axial-rich ellagitannin. HMBC correlations appeared
at H-3/C-21, C-21/H-23, H-6/C-34, and C-34/H-32 (SI-3.8) to
show that the HHDP group bridged between O-3 and O-6.
ROESY spectra displayed correlations at H-2/H-23 and H-4/H-32.
These correlations indicated the R-axial chirality of the HHDP
group, because the correlations were structurally accountable
when the axial chirality was R. With S-axial chirality, the angle of
the HHDP group over the pyranose was completely different in a
computationally generated model, in which the atomic distances
between H-2 and H-32 and between H-4 and H-23 were shorter
than those between H-2 and H-23 and between H-4 and H-32. In
The production ratio of the compounds corresponding to the
peaks A–E were A/B/C/D/E = 14/14/38/32/2 after consideration of
the molar absorbance coefficients of 6–10 at 254 nm (SI-3.3). This
ratio displayed the facile formation of the 4,6-O-HHDP group
(peaks A–C), which was 66% among the peaks A–E. An
astonishing fact was the unexpected formation of the 1,6-bridge
as the second best, and the detection of the 3,6-bridged
compound.
In conclusion, we investigated the oxidation of the b-PGG
analog, 1,2,3,4,6-penta-O-(4-O-benzylgalloyl)-b-D-glucose (5),
and determined the structures of five products provided by the
This article is protected by copyright. All rights reserved.

10.1002/anie.201708703
Angewandte Chemie International Edition
COMMUNICATION
[3]
[4]
T. Okuda, T. Yoshida, T. Hatano, H. Ito in Chemistry and Biology of
Ellagitannins (Eds.: S. Quideau), World Scientific, Singapore, 2009, pp. 1–54.
T. Yoshida, T. Hatano, H. Ito, T. Okuda in Studies in Natural Products
Chemistry, Vol. 23 (Eds.: Atta-ur-Rahman), Elsevier B. V., Amsterdam,
2000, pp. 395–453.
oxidation with their production ratio. In terms of synthesis of
natural ellagitannins, the results indicated casuarictin (3),
tellimagrandin II (4), and davidiin (2) could be synthesized in two
steps from 5 despite the requirement of HPLC-separation. More
importantly, the results demonstrated the following features in the
non-enzymatic HHDP formation on glucose in the case where
each galloyl group was protected by a benzyl group at the 4-O
position. (1) The best position to couple the gallates was between
the 4- and 6-positions. The axial chirality of the obtained HHDP
group was S. (2) The second best was the 1,6-position with S-
axial chirality. (3) After the production of the 4,6-O-(S)-HHDP
group, formation of the second bridge was possible at comparable
1,2- and 2,3-positions with R- and S-axial chirality, respectively.
(4) Although minor in the ratio, it is important to note the
occurrence of the 3,6-O-HHDP compound with R-axial chirality.
The facile formation of the 4,6-O-(S)-HHDP group is in
agreement with the structural distribution of natural ellagitannins.
The R-preference in the 1,2-coupling was newly discovered.
Although our previous structural revision erased the sole
ellagitannin of which the axial chirality of the 1,2-O-HHDP group
had been discussed,[30] natural products with 1,2-O-(R)-HHDP
group may be discovered in the future. For the occasion, the
spectral data for 22 (SI-3.19 and 4.13) will be used for
identification. The production of the 1,6-O-HHDP group at a
surprisingly high ratio shows the possibility of simultaneous
conformational inversion of the pyranose ring into an axial-rich
form and the formation of the HHDP group. With the clarified 3,6-
O-HHDP formation, the results indicate flexibility in the
conformation of the pyranose ring in 5. The bulk of the five
consecutive 4-O-Bn-galloyl and methylene-O-(4-O-Bn-galloyl)
groups may increase the population of the axial rich conformers
with respect to the all equatorial one, as previously demonstrated
for pyranosides and inositols bearing bulky silyl ethers.[38]
[5]
[6]
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Wien, 1982, pp. 1–46.
[13] R. Niemetz, G. Schilling, G. G. Gross, Chem. Commun. 2001, 35.
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Acknowledgements
The MEXT in Japan supported the program for the Strategic
Research Foundation at Private Universities (S1311046), JSPS
KAKENHI (Grant Number JP16H01163 in Middle Molecular
Strategy, and JP16KT0061) partly supported this work. We thank
Prof. T. Hatano (Okayama Univ. Japan), Osaka Synthetic
Chemical Laboratories, Inc., and Prof. T. Hatakeyama (Kwansei
Gakuin Univ. Japan) for provision of NMR data of davidiin,
provision of EDCI·HCl, and the support of measuring molar
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Keywords: Natural products • Oxidation • C-C coupling •
Polyphenols • Ellagitannins
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This article is protected by copyright. All rights reserved.

10.1002/anie.201708703
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Coupled at surprising sites: The
1st step for the structural diversity of
ellagitannins is oxidation of b-
pentagalloylglucose (b-PGG). This
study revealed that oxidation of a b-
PGG analog coupled the galloyl
groups at the 4,6-, 1,6-, 1,2-, 2,3-,
and 3,6-positions with high
diastereoselectivity in each site. The
1,6- and 3,6-coupled products
demonstrate that even skeletons with
an axial-rich glucose core may
generate non-enzymatically.
Seiya Ashibe, Kazutada Ikeuchi, Yuji
Kume, Shinnosuke Wakamori, Yuri
Ueno, Takashi Iwashita, and Hidetoshi
Yamada*
Page No. – Page No.
Nonenzymatic Oxidation of a
Pentagalloylglucose Analog to
Ellagitannins
This article is protected by copyright. All rights reserved.